International Immunology, Vol. 13, No. 1, 13-22,
January 2001
© 2001 Japanese Society for Immunology
The involvement of the proto-oncogene p120 c-Cbl and ZAP-70 in CD2-mediated T cell activation
1 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
2 Laboratory of Lymphocyte Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
Correspondence to: B. E. Bierer, National Institutes of Health, 10 Center Drive, Building 10, Bethesda, MD 20892, USA
The CD2 co-receptor expressed on the surface of T lymphocytes is able to stimulate T cell activation, proliferation and cytokine production in the absence of direct engagement of the antigen-specific TCR. Engagement of human CD2 by mitogenic pairs of anti-CD2 mAb induces tyrosine phosphorylation of a number of intracellular proteins including a 120 kDa phosphoprotein that we identify as the proto-oncogene c-Cbl. Rapidly tyrosine phosphorylated following stimulation of a number of cell surface receptors, c-Cbl is an adaptor protein that has been shown to associate with a complex of intracellular signaling molecules, and to mediate both positive and negative regulatory effects. Here we show that, like TCR–CD3 stimulation, stimulation of CD2 enhanced the association of c-Cbl with both Crk(L) and the p85 subunit of phosphatidylinositol-3 kinase. Overexpression of wild-type c-Cbl protein inhibited both CD2and CD3-induced NF-AT transcriptional activity, suggesting that CD2 signaling is also negatively regulated by c-Cbl. The inhibitory effect of c-Cbl depended upon its N-terminal phosphotyrosine-binding domain, the domain that has been shown to be required for inhibition of the Syk/ZAP-70 family kinases. In Syk– Jurkat T cells stably expressing wild-type ZAP-70, CD2 stimulation induced only a minimal increase in ZAP-70 tyrosine phosphorylation. Nevertheless, ZAP-70 kinase was required for CD2-mediated NF-AT transcriptional activity. Thus, CD2-mediated NF-AT transcriptional activity appears to depend upon ZAP-70/Syk kinases and to be negatively regulated by c-Cbl.
Keywords: Crk, NF-AT, phosphatidylinositol-3 kinase, signal transduction, Syk, T lymphocytes, ZAP-70
3 Present address: Department of Immunology and Hemostasis, Genetics Institute, Inc., Andover, MA 01810, USA
The first two authors contributed equally to this work
Transmitting editor: T. Watanabe
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